AT1 receptor antagonists

High blood pressure is recognized as a major risk factor for the development of stroke, myocardial infarction, congestive heart failure and renal insufficiency. For many years, the classification of the presence and severity of hypertension has been established by diastolic blood pressure measurements. Until the early 1990s, most of the hypertension trials have included patients solely on the identification of diastolic hypertension. Although life insurance companies had previously identified high systolic blood pressure as a potent predictor of early cardiac death at the turn of the 20th century, it was only in the mid-1970s that an increase in systolic blood pressure was clearly identified as a risk factor for cardiovascular morbidity and mortality regardless of age and gender [1]. Even though diastolic and systolic blood pressures are closely related when assessed in a population, the hypertension-related organ damage is more tightly related to systolic rather than to diastolic blood pressure values [1]. With the ageing of the population, the prevalence of hypertension reaches numbers that are becoming astounding. Nearly 50% of the population aged over 65 years is hypertensive, and up to 60% of these subjects present with isolated systolic hypertension (systolic blood pressure > 140 mmHg and diastolic blood pressure < 90 mmHg). Following the publication of the Systolic Hypertension in the Elderly Program (SHEP) Study, the well-encroached and popular belief that systolic blood pressure increases with age with the rule of thumb that the upper limit is 100 plus age should be considered ‘ancient history'. Indeed, not only have epidemiological studies shown that the degree of hypertension-related complications is directly related to the level of systolic blood pressure, but SHEP also showed that, in an elderly population with isolated systolic hypertension (average blood pressure 170.5 ± 9.5/76.7 ± 9.6 mmHg), administration of a thiazide diuretic (with or without a β-blocker) reduced blood pressure (144.0 ± 19/67.7 ± 10 mmHg) and cardiovascular morbidity by 32% compared with placebo [2]. More recent studies (Syst-EUR and Syst-China) using calcium channel blockers as anti-hypertensive agents showed similar results in other elderly populations with isolated systolic hypertension [3,4]. Isolated systolic hypertension most frequently indicates a stiffening of the large capacitance arteries as a consequence of vascular wall damage due to uncontrolled high blood pressure. Epidemiological studies show that diastolic blood pressure tends to decrease after age 50 years, whereas systolic blood pressure keeps increasing with age resulting in a widening of pulse pressure. The slopes of both pressure parameters evolving in opposite directions are proportional to the absolute blood pressure values measured before age 50 years [5]. Therefore, early and tight blood pressure control may prevent pulse pressure amplification associated with ageing. Despite compelling evidence calling for arterial blood pressure control, only one-quarter of the hypertensive population reaches target blood pressure values. Once identified, high blood pressure faces many hurdles on the way to normalization. First of all, the willingness to accept systolic blood pressure levels above the recommended values according to guidelines issued by national and international scientific societies represents one of the major barriers towards blood pressure control [6]. In most recent clinical trials, pharmacological treatments were able to lower diastolic pressure values below 90 mmHg, whereas the recommended goal was not achieved for systolic blood pressure. In these trials, the great majority of the patients remained above 140 mmHg, although the target for systolic blood pressure values was well known [7]. Second, it is more difficult to normalize systolic than diastolic blood pressure. Multiple drug regimens are usually necessary to normalize blood pressure as demonstrated by several recent trials. Therefore, combination therapy including blood pressure-lowering agents that offer additive cardiovascular benefit beyond blood pressure control without additional side-effects would definitely be of great significance to improve both doctor and patient compliance in order to reduce hypertension-related morbidity. In this issue of the journal, Klingbeil et al. [8] have assessed the potential of valsartan, an AT1 receptor blockade, to improve the vascular function of young essential hypertensive patients beyond the changes obtained with a thiazide diuretic for similar blood pressure reduction in a double-blind, randomized and placebo-controlled study. To assess vascular function, the augmentation index (AI) derived from the radial artery pressure wave has been recorded. Although not as familiar as pulse wave velocity (PWV) measurements, AI is strongly correlated with the well-validated estimate of arterial stiffness, PWV [9]. A transfer function was applied to generate a central aortic pressure wave from the radial recording. The elastic properties of large vessel walls determine the AI whose amplification is associated with increased left ventricular afterload and subsequent complications. In their study, the authors demonstrate that, for a similar blood pressure reduction, the AT1 receptor antagonist (ARB) reduces the AI much more compared to the diuretic, which was not different from the placebo. This result suggests that ARBs may provide a benefit on vascular wall function that extends beyond blood pressure reduction in this rather young hypertensive population. In this study of short duration, blood pressure was far from being controlled with either valsartan (80 mg/day) or with hydrochlorothiazide (25 mg/day); however, the two treatment arms reached similar blood pressure reduction. Unfortunately, no ambulatory blood pressure monitoring was performed. Therefore, we do not know whether blood pressure control over the 24 h was similar in both groups. This should be addressed in a future study to clearly demonstrate that the results presented here are totally pressure independent. What could the reasons be for a different vascular effect of the two treatment arms? The use of diuretics likely activates the renin–angiotensin system, which in turn contributes to functional and/or structural remodelling of the vascular tree. Both angiotensin II and aldosterone have trophic properties on vascular smooth muscle cells, as well on the extracellular matrix. Whether the large elastic arteries or the resistance vessels could primarily be affected cannot be singled out by AI assessment. Direct carotid pressure wave measurements would have been more desirable than the radial wave recordings. Indeed, generation of a central pressure wave using a transfer function relies on many assumptions and has not been validated with all the different classes of antihypertensive agents. Interaction between angiotensin II and the sympathetic nervous system may also have played a role in the differences observed in the study, although the resting heart rate was not significantly higher in the diuretic arm. Again, absence of circadian control of haemodynamic parameters does not allow definitive conclusions to be drawn. In conclusion, Klingbeil et al. [8] have demonstrated a very interesting effect of an AT1 receptor antagonist on the elasticity of the arterial wall, which appears to be partly independent of the blood pressure-lowering effect. Future studies will indicate whether improvement in the vascular properties translates into a clinical benefit.